Thyroid hormones act on every cell in the body. They are responsible for maintaining body temperature, growth, heart rate, and also for modulating our bodies’ responses to other hormones. Therefore, they are important regulators of metabolism, and are crucial to the proper development and function of most body organs including the brain.
Over 200 million people worldwide suffer from thyroid hormone deficiencies or hypothyroidism – a condition that manifests as mental slowness, depression, fatigue and weight gain. The condition is treated using synthetic thyroxine that is administered as tablets available from a variety of brands. However, different brands of synthetic thyroxine have been found to be highly variable from each other. Therefore, when patients switch brands, they can receive either too much or too little of this life-saving hormone. Dr. Mugesh’s laboratory at the Department of Inorganic and Physical Chemistry (Indian Institute of Science, Bangalore) has recently come up with an explanation for this highly variable therapeutic property of generic thyroxine between brands.
In their recent paper published in the journal Angewandte Chemie, Prof. Mugesh and his student Santanu Mondal discovered that synthetic thyroxine could be present in two different forms called ‘polymorphs’ (poly= multiple; morphs= forms) that vary in their 3-dimensional structures. Using sophisticated techniques such as single-crystal and high-resolution powder X-ray diffraction (PXRD), Raman spectroscopy, solid-state nuclear magnetic resonance (SS-NMR) spectroscopy, and differential scanning calorimetry (DSC), the scientists studied the stability and molecular conformations of these two polymorphs.
The solubility measurements showed that the polymorphs dissolve differently in water. This not only causes them to be differentially absorbed in the human body, but could also ultimately affect their activity in the body. Thyroxine molecules contain several iodine atoms attached to their amino acids. The activity of this hormone in the body is regulated by the selective removal of these iodine atoms by a trio of enzymes named Dio1, 2 and 3. The conformational differences between the two polymorphic forms of thyroxine affects the chemical nature of their Carbon – Iodine bonds, and hence their metabolism by the Dio enzymes.
Synthetic thyroxine is a drug with a narrow therapeutic index, which means that small changes in its concentrations or activity can lead to large effects. Therefore, the small conformational variations between the two polymorphs affect not only the hormone’s dissolution in water and bioavailability, but also its metabolism and downstream effects on the body. This could be the leading cause of the major differences observed in the therapeutic properties of different brands of the drug.
“We do need further studies in animal models to confirm our findings”, says Prof. Mugesh. Understanding the properties of thyroxine conformational polymorphs will be the first step in designing a more uniform formulation of the drug to cut down on side effects when patients switch between brands of thyroxine tablets.
About the authors
Dr. Govindasamy Mugesh is a Professor at the Department of Inorganic and Physical Chemistry at the Indian Institute of Science, Bangalore.
Santanu Mondal is a PhD student working under the guidance of Prof. Mugesh.